In 2001, 800,000 children worldwide became HIV infected, mostly through mother-to-child transmission (MTCT). Most MTCT events occurred in Africa. HIV can be transmitted during gestation, intrapartum, or by breastfeeding. While short courses of antiviral drugs in the perinatal period have significantly decreased MTCT in developing countries, breastfeeding had a negative impact on the benefits of this drug treatment. Breastfeeding can account for a substantial proportion of overall MTCT; however, avoidance of breastfeeding is not a realistic public health option in resource-poor settings such as ours in South Africa. Clearly, postnatal HIV transmission by breast milk needs to be addressed. Our long-range goal is to prevent HIV transmission through breastfeeding by passive immunization with combinations of human neutralizing monoclonal antibodies (nmAbs). We passively administered triple or quadruple combinations of human nmAbs targeting conserved HIV Env epitopes to newborn monkeys before and after oral challenge with chimeric simian-human immunodeficiency viruses (SHIVs) that encoded different HIV envelope genes. Of 31 nmAb-treated infant monkeys, 22 were completely protected. In cultured cells, such nmAbs, isolated from individuals infected with HIV clade B, provided potent cross-clade neutralization of primary HIV clade A, B, C, and D isolates. Thus, we postulate that given their safety and long half-lives in adult volunteers and their efficacy in neonatal monkeys, human nmAbs given at regular, long intervals can protect babies breastfed by HIV-positive mothers during the period of nursing. The goal of this application is to conduct a Phase I trial with human nmAbs in HIV-exposed but uninfected infants. We plan to use a combination of human nmAbs that will have been tested already for safety and pharmacokinetics in adult volunteers and that has been effective in neonatal primates challenged with SHIV, criteria that have been met by human nmAbs F105, 2G12, and 2F5. A fourth nmAb, 4E10, may fulfill these criteria soon - this nmAb is potent, safe, and highly effective in neonatal primates. The Specific Aims are to: 1. Determine the safety of nmAbs given by intramuscular administration to HIV-exposed, but uninfected neonates in a triple (or quadruple) combination regimen. All infants will also receive perinatal nevirapine. 2. Establish the pharmacokinetics of each of the human nmAbs given in the combination regimen. 3. Determine the doses for each nmAb in the combination that provide levels at 14 days capable of achieving greater than or equal too 90% neutralization of autologous maternal HIV isolates. 4. Determine the safety of a multiple dosing regimen to be used in follow-up trials. These studies will lay the groundwork for a Phase III passive immunoprophylaxis trial, in which we will test whether MTCT via breast milk can be reduced safely and whether intrapartum HIV transmission can be lowered also.